Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cellular susceptibility of cancer cells to histone deacetylase (HDAC) inhibitors is increased by the etopic expression of oncogenic Ras. However, the ability of HDAC inhibitors to regulate the apoptotic pathway in human breast cancer cells is still not completely understood. In this study, the anti-proliferative effects of apicidin were compared in H-ras-transformed human breast epithelial (MCF10A-ras) and non-transformed epithelial (MCF10A) cells. MCF10A-ras cells showed a significantly higher growth rate than MCF10A cells. Apicidin significantly increased the levels of acetylated histone H3 and H4 in both cell lines. Western blot analysis and flow cytometry were used to determine if the anti-proliferative effects of apicidin in MCF10A and MCF10A-ras cells could be mediated by modulating the cell cycle. Apicidin attenuated the expression of cyclin E and CDK2 in MCF10A cells, decreased cyclin D1 and cyclin E levels in MCF10A-ras cells, and increased the levels of CDK inhibitors, p21WAF1/Cip1 and p27Kip1, in both cell lines. Notably, the levels of hyperphosphorylation of the Rb protein levels were lower in the MCF10A-ras cells after apicidin treatment. Studies on the regulation of apoptosis showed that apicidin induces the up-regulation of p53 and the downstream activation of ERK in MCF10A-ras cells. The up-regulation of p53 promoted Bax expression leading to activation of caspases-9 and -6, and eventually to apoptosis in MCF10A-ras cells. In addition, apicidin significantly increased the levels of ERK1/2 phosphorylation in MCF10A-ras cells. Therefore, the apicidin-mediated ERK pathway appears to play an important role in modulating the pro-apoptotic pathway in MCF10A-ras cells.
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PMID:Effects of apicidin, a histone deacetylase inhibitor, on the regulation of apoptosis in H-ras-transformed breast epithelial cells. 1828 80

Heregulin beta-1 (HRG) is an extracellular ligand that activates mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI3K)/Akt signaling pathways through ErbB receptors. MAPK and Akt have been shown to phosphorylate the estrogen receptor (ER) at Ser-118 and Ser-167, respectively, thereby mimicking the effects of estrogenic activity such as estrogen responsive element (ERE)-dependent transcription. In the current study, integrative analysis was performed using two tiling array platforms, comprising histone H3 lysine 9 (H3K9) acetylation and RNA mapping, together with array comparative genomic hybridization (CGH) analysis in an effort to identify HRG-regulated genes in ER-positive MCF-7 breast cancer cells. Through application of various threshold settings, 333 (326 up-regulated and 7 down-regulated) HRG-regulated genes were detected. Prediction of upstream transcription factors (TFs) and pathway analysis indicated that 21% of HRG-induced gene regulation may be controlled by the MAPK cascade, while only 0.6% of the gene expression is controlled by ERE. A comparison with previously reported estrogen (E2)-regulated gene expression data revealed that only 12 common genes were identified between the 333 HRG-regulated (3.6%) and 239 E2-regulated (5.0%) gene groups. However, with respect to enriched upstream TFs, 4 common TFs were identified in the 14 HRG-regulated (28.6%) and 13 E2-regulated (30.8%) gene groups. These results indicated that while E2 and HRG may induce common TFs, the regulatory mechanisms that govern HRG- and E2-induced gene expression differ.
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PMID:Integrative genome-wide expression analysis bears evidence of estrogen receptor-independent transcription in heregulin-stimulated MCF-7 cells. 1835 Jan 42

Gene regulation by steroid hormones involves genomic and non-genomic signaling pathways and the relationship between these two pathways is unknown. Genomic actions are often mediated by binding of the ligand-activated hormone receptors to hormone responsive elements (HREs) followed by recruitment of co-regulators, remodeling of chromatin and formation of the transcription initiation complex. The non-genomic effects of steroid hormones involve the rapid and transient activation of several kinase cascades often mediated by a subpopulation of "nuclear" receptors located in the cytoplasmic side of the cell membrane. The progesterone effect on breast cancer cell proliferation involves activation of the Src/Ras/Erk cascade mediated by a specific interaction between two domains of the N-terminal half of PR and the ligand-binding domain of ERalpha. Unexpectedly, selective inhibition of Erk, or its target kinase Msk1, interferes with chromatin remodeling and blocks MMTV transcriptional activation. A complex of activated PR, Erk and Msk1 is recruited to promoter already 5 min after hormone treatment and phosphorylates histone H3 at serine 10, leading to displacement of HP1gamma, as a requisite for recruitment of Src1, chromatin remodeling complexes (hSnf2h and Brg1) and RNA polymerase II. Thus, activation of signaling cascades in the cytoplasm is essential for chromatin remodeling and transcriptional activation of a subset of steroid hormone target genes.
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PMID:Convergence on chromatin of non-genomic and genomic pathways of hormone signaling. 1841 38

Sustained over-expression of Aurora A (AurA), centrosome amplification, chromosomal instability, and aneuploidy are salient features that occur in high frequency in human breast premalignant stages and in primary ductal breast cancer (BC), as well as in 17beta-estradiol (E2)-induced oncogenesis in animal models. We have reported that AurA/B protein expression increases 8.7- and 4.6-fold, respectively, in primary E2-induced male Syrian hamster uterine stem cell-like tumors of the kidney (EUTK) when compared with cholesterol-treated control kidneys. Upon a 10-day E2-withdrawal or coadministration of tamoxifen citrate, a 78-79% and 81-64% reduction in AurA/B protein expression, respectively, were observed in primary tumors when compared with tumors from animals continuously exposed to E2. These data indicate that AurA/B expression is regulated by estrogens via estrogen receptor alpha. To determine whether this E2-induced over-expression of the Aur kinases may contribute to the alterations observed during oncogenesis via their phosphorylation of specific substrates, we analyzed the protein expression of histone H3 and targeting protein for Xklp2 (TPX2). Histone H3 and TPX2 were significantly over-expressed 3.7- and 1.6-fold, respectively, in E2-induced tumors when compared with cholesterol-treated control kidney samples. Immunohistochemistry revealed that TPX2 protein expression was essentially confined to tumor foci cells. Collectively, these data indicate that over-expression of AurA/B is under estrogen control and that the deregulation of Aur kinase protein substrates is implicated in eliciting the alterations observed during oncogenesis.
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PMID:Expression of selected Aurora A kinase substrates in solely estrogen-induced ectopic uterine stem cell tumors in the Syrian hamster kidney. 1849 64

Germline mutations of BRCA1 predispose women to breast and ovarian cancers. However, the downstream mediators of BRCA1 function in tumor suppression remain elusive. We found that human BRCA1-associated breast cancers have lower levels of SIRT1 than their normal controls. We further demonstrated that mammary tumors from Brca1 mutant mice have low levels of Sirt1 and high levels of Survivin, which is reversed by induced expression of Brca1. BRCA1 binds to the SIRT1 promoter and increases SIRT1 expression, which in turn inhibits Survivin by changing the epigenetic modification of histone H3. Absence of SIRT1 blocks the regulation of Survivin by BRCA1. Furthermore, we demonstrated that activation of Sirt1 and inhibition of Survivin expression by resveratrol elicit a more profound inhibitory effect on Brca1 mutant cancer cells than on Brca1-wild-type cancer cells both in vitro and in vivo. These findings suggest that resveratrol treatment serves as an excellent strategy for targeted therapy for BRCA1-associated breast cancer.
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PMID:Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. 1895 Oct 80

Tumor migration/invasion is the main cause of tumor progression and STAT3 is needed to enhance tumor migration/invasion by up-regulating MMP-9. Thus, agents that inhibit STAT3 activation may be used as an anticancer drug. We present herein that 6-methyl-2-propylimino-6, 7-dihydro-5H-benzo [1, 3]-oxathiol- 4-one (LYR71) , a derivative of trimeric resveratrol, has an anticancer activity through inhibition of STAT3 activation. We found that LYR71 suppressed STAT3 activation and inhibited the expression and activity of MMP-9 in RANTES-stimulated breast cancer cells. In addition, LYR71 reduced RANTES-induced MMP-9 transcripts by blocking STAT3 recruitment, dissociating p300 and deacetylating histone H3 and H4 on the MMP-9 promoter. Furthermore, LYR71 inhibited tumor migration/invasion in RANTES-treated breast cancer cells and consequently blocked tumor progression in tumor-bearing mice. Taken together, the results of this study suggest that LYR71 can be therapeutically useful due to the inhibition effect of STAT3-mediated MMP-9 expression in breast cancer cells.
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PMID:LYR71, a derivative of trimeric resveratrol, inhibits tumorigenesis by blocking STAT3-mediated matrix metalloproteinase 9 expression. 1898 9

Withaferin A (WA) is derived from the medicinal plant Withania somnifera that has been safely used for centuries in the Indian Ayurvedic medicine for treatment of various ailments. We now demonstrate that WA treatment causes G2 and mitotic arrest in human breast cancer cells. Treatment of MDA-MB-231 (estrogen-independent) and MCF-7 (estrogen-responsive) cell lines with WA resulted in a concentration- and time-dependent increase in G2-M fraction, which correlated with a decrease in levels of cyclin-dependent kinase 1 (Cdk1), cell division cycle 25C (Cdc25C) and/or Cdc25B proteins, leading to accumulation of Tyrosine15 phosphorylated (inactive) Cdk1. Ectopic expression of Cdc25C conferred partial yet significant protection against WA-mediated G2-M phase cell cycle arrest in MDA-MB-231 cells. The WA-treated MDA-MB-231 and MCF-7 cells were also arrested in mitosis as judged by fluorescence microscopy and analysis of Ser10 phosphorylated histone H3. Mitotic arrest resulting from exposure to WA was accompanied by an increase in the protein level of anaphase promoting complex/cyclosome substrate securin. In conclusion, the results of this study suggest that G2-M phase cell cycle arrest may be an important mechanism in antiproliferative effect of WA against human breast cancer cells.
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PMID:Ayurvedic medicine constituent withaferin a causes G2 and M phase cell cycle arrest in human breast cancer cells. 1900 81

B-cell Translocation Gene 2 (BTG2/TIS21/PC3) is an anti-proliferative tumor suppressor gene whose expression is significantly reduced in breast carcinomas, and in MCF-7 and T-47D breast cancer cell lines treated with estradiol (E2). In this study the mechanisms involved in E2 down regulation of BTG2 gene expression were examined. Depletion of ERalpha by siRNA indicated that the receptor is required for E2 down regulation of BTG2 mRNA levels, and cycloheximide experiments indicated that the effect of E2 on BTG2 expression was independent of intermediary protein synthesis. Chromatin immunoprecipitation analyses revealed that ERalpha interacts with the BTG2 promoter in a ligand-independent fashion whereas transfection experiments indicated that ERalpha's DNA and ligand binding domains are required for E2 repression of BTG promoter activity. Surprisingly, histone deacetylase (HDACs) activity is essential for basal expression as evidenced by trichostatin A inhibition of BTG2 mRNA levels. Estradiol treatment did not alter histone H3 acetylation although it did induce displacement of RNA polymerase II from the BTG2 gene. Depletion of the ER specific corepressor REA (Repressor of Estrogen Receptor Activity) significantly abrogated E2-mediated BTG2 repression. Taken together, our results reveal a requirement of HDAC activity for basal BTG2 expression and the ERalpha-REA interaction for estrogen repression of the BTG2 gene. The ability of E2-bound ERalpha and REA to suppress BTG2 expression indicates a positive role for this corepressor in regulation of breast cancer cell proliferation.
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PMID:Estradiol downregulation of the tumor suppressor gene BTG2 requires estrogen receptor-alpha and the REA corepressor. 1911 54

Both prolactin (PRL) and estrogen (E2) are involved in the pathogenesis and progression of mammary neoplasia, but the mechanisms by which these hormones interact to exert their effects in breast cancer cells are not well understood. We show here that PRL is able to activate the unliganded estrogen receptor (ER). In breast cancer cells, PRL activates a reporter plasmid containing estrogen response elements (EREs) and induces the ER target gene pS2. These actions are blocked by the antagonist ICI 182,780, showing that ER is required for the PRL-mediated effect. Moreover, PRL leads to phosphorylation of ERalpha in serine-118 (P-ERalpha), a modification related to the potentiation of ligand-independent transcriptional activation. In addition, PRL mimics the effect of E2 on target gene expression by inducing cyclical recruitment of ERalpha and P-ERalpha to ERE-containing promoters, resulting in recruitment of co-activators and acetylation of histone H3. Finally, PRL induces expression of c-Myc and Cyclin D1 and leads to increased cell proliferation, which is specifically antagonized by ICI 182,780 or ERalpha depletion. These results show that ligand-independent ERalpha activation appears to be an important component of the proliferative and transcriptional actions of PRL in breast cancer cells.
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PMID:Activation of the unliganded estrogen receptor by prolactin in breast cancer cells. 1916 77

p21 loss has been implicated in conferring oncogenic activity to known tumor suppressor gene KLF4 and cancer drug tamoxifen. Regulators of p21, therefore, play critical roles in tumorigenesis. Here, we report that X-linked tumor suppressor FOXP3 is essential for p21 expression in normal epithelia and that lack of FOXP3 is associated with p21 down-regulation in breast cancer samples. A specific FOXP3 binding site in the intron 1 is essential for p21 induction by FOXP3. FOXP3 specifically inhibited binding of histone deacetylase 2 (HDAC2) and HDAC4 to the site and increased local histone H3 acetylation. Short hairpin RNA silencing of either HDAC2 or HDAC4 is sufficient to induce p21 expression. Our data provides a novel mechanism for transcription activation by FOXP3 and a genetic mechanism for lack of p21 in a large proportion of breast cancer.
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PMID:FOXP3 up-regulates p21 expression by site-specific inhibition of histone deacetylase 2/histone deacetylase 4 association to the locus. 1927 56


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